Are we SHARP enough? The importance of adequate patient selection in sorafenib treatment for hepatocellular carcinoma

Labeur, Tim A.; Cate, David W. G. ten; Takkenberg, R. Bart; Azahaf, Hicham; Oijen, Martijn G.H. van; Delden, Otto M. van; Man, Robert A. de; Vugt, Jeroen L.A. van; IJzermans, Jan N.M.; Eskens, Ferry A.L.M.; Klümpen, Heinz‐Josef

doi:10.1080/0284186x.2018.1479070

Cited by 14 publications

(13 citation statements)

References 25 publications

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“…Sorafenib, a tyrosine kinase inhibitor, is recommended for patients with advanced hepatocellular carcinoma (HCC) and Child-Pugh class A liver function [1][2][3]. Nonetheless, real-life studies showed that sorafenib is still commonly (12%-44%) prescribed to patients with Child-Pugh B liver function [4][5][6][7][8][9][10][11][12][13][14]. Sorafenib undergoes hepatic metabolism and biliary excretion, which could potentially be influenced by concomitant liver cirrhosis [15].…”

Section: Discussionmentioning

confidence: 99%

“…This reflects the difficulty in recruiting and treating these patients, mainly due to the higher risk of cirrhosis-related adverse events. In a prior study, we extensively discussed this topic and pled for adherence to the current guidelines and restriction of sorafenib to patients with Child-Pugh A liver function [9]. Interestingly, one patient with a partial response to sorafenib had an OS of 26 months, showing that longer survival is possible in patients with Child-Pugh B and underscoring limitations of Child-Pugh as a prognostic tool when considering sorafenib.…”

Section: Drug Informationmentioning

confidence: 99%

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Sorafenib for Patients with Hepatocellular Carcinoma and Child-Pugh B Liver Cirrhosis: Lessons Learned from a Terminated Study

et al. 2019

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Lessons Learned Recruitment of patients with advanced hepatocellular carcinoma and Child‐Pugh B for sorafenib treatment and additional pharmacokinetic studies is challenging. Patients with Child‐Pugh B liver cirrhosis have high rates of cirrhosis‐related adverse events. Background Few data are available on the pharmacokinetics (PK) of sorafenib in patients with advanced hepatocellular carcinoma (HCC) and Child‐Pugh B liver cirrhosis. This study aimed to explore the sorafenib PK and its relationship with efficacy and toxicity in these patients. Methods Patients with advanced HCC and Child‐Pugh B7‐8 liver function were prospectively recruited at a tertiary center. Adverse events (AEs), progression‐free survival (PFS), and overall survival (OS) were recorded. Patients received a starting dose of 200 b.i.d. with toxicity‐adjusted dose escalation to a target dose of 400 mg b.i.d. with PK sampling at fixed time points. Results Between May 2014 and March 2017, 12 patients were screened, of whom 7 progressed to a terminal stage during the screening (n = 6) or shortly after recruitment (n = 1). The five included patients had median PFS of 3.8 months (range, 1.7–10.8) and OS of 7.4 months (range, 1.7–25.8). Three patients had severe AEs and one patient had a partial response with an OS of 25.8 months. In 2017, the trial was aborted for lack of accrual. Conclusion Because of low accrual, no conclusion can be drawn on the sorafenib PK in patients with advanced HCC and Child‐Pugh B liver cirrhosis. The poor survival and frequent cirrhosis‐related AEs suggest limited benefit for most of these patients.

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Section: Discussionmentioning

confidence: 99%

Section: Drug Informationmentioning

confidence: 99%

Sorafenib for Patients with Hepatocellular Carcinoma and Child-Pugh B Liver Cirrhosis: Lessons Learned from a Terminated Study

et al. 2019

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“…Sorafenib, a molecular targeted drug for HCC, was shown to be effective for patients with well-preserved liver function (Child-Pugh A) although poor outcomes were significantly associated with Child-Pugh B patients [31]. A natural substance, betulinic acid, sensitized pancreatic ductal adenocarcinoma cells to sorafenib accompanying the downregulation of c-MYC [32].…”

Section: Discussionmentioning

confidence: 99%

HBx and c-MYC Cooperate to Induce URI1 Expression in HBV-Related Hepatocellular Carcinoma

Tsuchiya

Amisaki

Takenaga

et al. 2019

IJMS

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Unconventional prefoldin RNA polymerase II subunit 5 interactor (URI1) has emerged as an oncogenic driver in hepatocellular carcinoma (HCC). Although the hepatitis B virus (HBV) represents the most common etiology of HCC worldwide, it is unknown whether URI1 plays a role in HBV-related HCC (HCC-B). In the present study, we investigated URI1 expression and its underlying mechanism in HCC-B tissues and cell lines. URI1 gene-promoter activity was determined by a luciferase assay. Human HCC-B samples were used for a chromatin immunoprecipitation assay. We found that c-MYC induced URI1 expression and activated the URI1 promoter through the E-box in the promoter region while the HBx protein significantly enhanced it. The positivity of URI1 expression was significantly higher in HCC-B tumor tissues than in non-HBV-related HCC tumor tissues, suggesting that a specific mechanism underlies URI1 expression in HCC-B. In tumor tissues from HCC-B patients, a significantly higher level of c-MYC was recruited to the E-box than in non-tumor tissues. These results suggest that HBx and c-MYC are involved in URI1 expression in HCC-B. URI1 expression may play important roles in the development and progression of HCC-B because HBx and c-MYC are well-known oncogenic factors in the virus and host, respectively.

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“…It is currently the most widely-used and studied systemic therapy. However, its efficacy is at present suboptimal and its toxicity, especially in patients with liver dysfunction [89], offers some additional reason for the use of LDTs to be stretched.…”

Section: Current State Of Liver Directed Therapies Associated Withmentioning

confidence: 99%

Current State of Liver-Directed Therapies and Combinatory Approaches with Systemic Therapy in Hepatocellular Carcinoma (HCC)

Viveiros

Riaz

Lewandowski

et al. 2019

Cancers

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The increasing set of liver-directed therapies (LDT) have become an integral part of hepatocellular carcinoma (HCC) treatment. These range from percutaneous ablative techniques to arterial embolization, and varied radiotherapy strategies. They are now used for local disease control, symptom palliation, and bold curative strategies. The big challenge in the face of these innovative and sometimes overlapping technologies is to identify the best opportunity of use. In real practice, many patients may take benefit from LDT used as a bridge to curative treatment such as resection and liver transplantation. Varying trans-arterial embolization strategies are used, and comparison between established and developing technologies is scarce. Also, radioembolization utilizing yttrium-90 (Y-90) for locally advanced or intermediate-stage HCC needs further evidence of clinical efficacy. There is increasing interest on LDT-led changes in tumor biology that could have implications in systemic therapy efficacy. Foremost, additional to its apoptotic and necrotic properties, LDT could warrant changes in vascular endothelial growth factor (VEGF) expression and release. However, trans-arterial chemoembolization (TACE) used alongside tyrosine-kinase inhibitor (TKI) sorafenib has had its efficacy contested. Most recently, interest in associating Y-90 and TKI has emerged. Furthermore, LDT-led differences in tumor immune microenvironment and immune cell infiltration could be an opportunity to enhance immunotherapy efficacy for HCC patients. Early attempts to coordinate LDT and immunotherapy are being made. We here review LDT techniques exposing current evidence to understand its extant reach and future applications alongside systemic therapy development for HCC.

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Are we SHARP enough? The importance of adequate patient selection in sorafenib treatment for hepatocellular carcinoma

Abstract: Landmark trial outcomes of sorafenib for HCC are reproducible in daily practice, provided that the SHARP eligibility criteria are respected. Based on the findings of this and previous studies, sorafenib usage should be restricted to Child-Pugh A patients.

Cited by 14 publications

References 25 publications

Sorafenib for Patients with Hepatocellular Carcinoma and Child-Pugh B Liver Cirrhosis: Lessons Learned from a Terminated Study

Sorafenib for Patients with Hepatocellular Carcinoma and Child-Pugh B Liver Cirrhosis: Lessons Learned from a Terminated Study

HBx and c-MYC Cooperate to Induce URI1 Expression in HBV-Related Hepatocellular Carcinoma

Current State of Liver-Directed Therapies and Combinatory Approaches with Systemic Therapy in Hepatocellular Carcinoma (HCC)

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